The predictive value of left ventricular global longitudinal strain in normotensive critically ill septic patients

Objective Evaluation of left ventricular systolic function using speckle tracking echocardiography is more sensitive than conventional echocardiographic measurement in detecting subtle left ventricular dysfunction in septic patients. Our purpose was to investigate the predictive significance of left ventricular global longitudinal strain in normotensive septic intensive care patients. Methods This observational, prospective cohort study included septic normotensive adults admitted to the intensive care unit between June 1, 2021, and August 31, 2021. Left ventricular systolic function was measured using speckle-tracking echocardiography within 24 hours of admission. Results One hundred fifty-two patients were enrolled. The intensive care unit mortality rate was 27%. Left ventricular global longitudinal strain was less negative, which indicated worse left ventricular function in non-survivors than survivors (median [interquartile range], -15.2 [-17.2 - -12.5] versus -17.3 [-18.8 - -15.5]; p < 0.001). The optimal cutoff value for left ventricular global longitudinal strain was -17% in predicting intensive care unit mortality (area under the curve, 0.728). Patients with left ventricular global longitudinal strain > -17% (less negative than -17%, which indicated worse left ventricular function) showed a significantly higher mortality rate (39.2% versus 13.7%; p < 0.001). According to multivariate analysis, left ventricular global longitudinal strain was an independent predictor of intensive care unit mortality [OR (95%CI), 1.326 (1.038 - 1.693); p = 0.024], along with invasive mechanical ventilation and Glasgow coma scale, APACHE II, and SOFA risk scores. Conclusion Impaired left ventricular global longitudinal strain is associated with mortality and provided predictive data in normotensive septic intensive care patients.


INTRODUCTION
Sepsis is a major global challenge associated with high mortality rates in intensive care unit (ICU) patients. (1) Sepsis-induced cardiomyopathy has been identified as one of the major factors leading to death. (2) Approximately 85% of septic patients admitted to the ICU have cardiac involvement, which is associated with hospital mortality. (3) Two-dimensional echocardiography is a noninvasive, low-cost imaging technique for evaluating cardiac function in sepsis. (4) Although left ventricular ejection fraction (LVEF) obtained from conventional echocardiography is the most commonly used method to assess left ventricle (LV) systolic function, its fundamental limitation is the inability to detect subtle cardiac dysfunction. (5) Strain measurement using speckletracking echocardiography is a recently developed technique to assess cardiac function. (5) Compared with conventional echocardiography measurement, this method is a more sensitive, reliable, and reproducible modality for assessing LV systolic function, particularly for deducing subtle LV dysfunction in the early stage of the disease. (6,7) Furthermore, left ventricular global longitudinal strain (LVGLS) has been shown to be a powerful predictor of cardiovascular events and all-cause mortality. (7) Accordingly, LVGLS measured by speckletracking echocardiography might be a good surrogate of intrinsic LV systolic function, contrary to LVEF.
There are reports investigating the association of LVGLS with outcomes in patients with sepsis. (6,8,9) However, a limited number of studies address the predictive value of LVGS in normotensive septic patients. (2) Therefore, our purpose was to analyze the predictive value of LVGLS in early-stage normotensive septic patients. In other words, we aimed to evaluate the predictive value of LVGLS within the first 24 hours of ICU patient admission. We hypothesized that impaired LVGLS is associated with increased mortality in normotensive septic patients in the ICU.

Study design and population
This observational, prospective cohort study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Kafkas University (May 26, 2021, No 80576354-050-99/179). Written informed consent was obtained from all patients or their legal representatives.
Consecutive adult patients with sepsis admitted to a tertiary medical ICU between June 1, 2021, and August 31, 2021, were included. Sepsis diagnosis was based on the Sepsis-3 criteria. (10) Baseline clinical variables, including demographics, comorbidities, hemodynamic parameters, Glasgow Coma Scale (GCS), (11) Sequential Organ Failure Assessment (SOFA), (12) and Acute Physiology and Chronic Health Evaluation II (APACHE II) (13) scores, were obtained and calculated within 24 hours of ICU admission. An echocardiographic examination was also performed for each subject within 24 hours of admission. Laboratory findings within the same timeframe were also analyzed.
The inclusion criteria were normotensive septic patients over the age of 18 years. The exclusion criteria were as follows: nonseptic patients and patients with septic shock; acute coronary syndrome; arrhythmias (atrial fibrillation and ventricular tachycardia); patients with metallic prosthetic mitral or aortic valves; and patients with coronavirus disease 2019 (COVID-19) infection.

Echocardiographic measurements
Echocardiographic images were obtained using Philips Epiq7 (Philips Ultrasound, WA, United States) based on the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) guidelines. (14) LV end-systolic, end-diastolic, and left atrium diameters were measured. Measurements of mitral inflow included the peak early (E-wave) and late (A-wave) diastolic filling velocities and calculation of the E/A ratio. The peak velocity of early diastolic mitral annular motion (e') as determined by pulsed wave Doppler was measured (the average of septal and lateral) in the apical four-chamber view. Left ventricular ejection fraction was measured using the modified Simpson's method described in the EACVI. (14) Speckle-tracking analysis was performed per the consensus document of the EACVI/ASE/Industry Task Force. (15) Left ventricular global longitudinal strain was analyzed by an experienced cardiologist, blinded to the outcome, using the onboard QLAB Advanced Quantification Software available in our echocardiography machine. While end-diastole was regarded as the peak R wave of the electrocardiogram, end-systole was estimated as aortic valve closure. Analysis of LV myocardial deformation was then performed from 2-dimensional grayscale loops by automatic tracking of myocardial speckles after manual selection of landmark points using apical views of the left ventricle. The region of interest was the endocardium (from the endocardial border to the myocardial midline). Left ventricular global longitudinal strain was calculated by averaging the negative peak of longitudinal strain from 17 ventricular segments from the apical 4-chamber, 3-chamber, and 2-chamber views ( Figure 1). Left ventricular global longitudinal strain was expressed as a percent change (%). Negative values of LVGLS represent myocardial contractility (the less negative value, the worse LVGLS performance).

Statistical analysis
The Statistical Package for the Social Sciences (SPSS) software version 20.0 (SPSS, Inc., Chicago, IL, United States) was used for statistical analysis. While the continuous variables were expressed as the mean values and standard deviation, categorical variables were presented as frequencies and percentages. Data were evaluated with the Kolmogorov-Smirnov test in terms of normal distribution. The independent t test was used to analyze normally distributed continuous data, and the Mann-Whitney U test was used to analyze non-normally distributed variables. As appropriate, categorical variables were compared with the chi-squared test or Fisher's exact test. Univariate regression analyses were performed for variables that were significantly different to identify the variables related to ICU mortality.
A multivariate logistic regression analysis, including the variables with p value < 0.05, was used to determine the independent risk factors for ICU mortality. Because our study was based on a predictive model and considered the background knowledge of the research, the cutoff value of 0.05 was chosen to better reveal clinically relevant covariates. Data are presented as odds ratios with the corresponding 95% confidence intervals (95%CI). A receiver operating characteristic (ROC) curve was used to detect the cutoff value of LVGLS in predicting ICU mortality. Additionally, Spearman correlation analysis was conducted between conventional echocardiographic parameters and LVGLS, as well as troponin value. The statistical significance level was accepted as two-tailed p values < 0.05.

RESULTS
One hundred seventy-four patients were admitted to the ICU during the study period. Twenty-two cases were excluded following exclusion criteria. Consequently, the final study population included 152 patients [median age 62 (interquartile range -IQR, 45 -73) years, 63.8% male].
A total of 41 (27%) patients died during hospitalization. During the ICU stay, 68% of the patients progressed to shock. Table 1 compares the baseline demographic, laboratory, and clinical variables between survivors and non-survivors. Non-survivors were older than survivors (age [IQR], 68 years [48 -77] versus 60 years [44 -70]; p = 0.016). The percentage of patients with invasive mechanical ventilation (IMV) was higher in non-survivors than in survivors (46.3% versus 13,5%; p < 0.001). However, there were no significant differences in sex, hospital stay, BMI, initial vital signs, or laboratory findings.
A cutoff value for LVGLS was calculated using ROC analysis to predict ICU mortality (Figure 2). The area under the curve was 0.73, and the optimal cutoff value was -17 (with a sensitivity of 73% and specificity of 57%). The median LVGLS was -16.95, similar to the cutoff value. Thus, the patients were classified into two groups according to the cutoff value (GLS ≥ -17%, n = 79 and GLS < -17%, n = 73). The comparison of the variables between these two groups is summarized in table 4.   According to Spearman correlation analysis, LVGLS was significantly correlated with LVEF and troponin value (-0.741, p < 0.001 and 0.202, p = 0.013) (Figure 3). No significant correlation was found between the remaining conventional echocardiographic parameters and LVGLS or troponin value.

DISCUSSION
Our study showed that impaired LVGLS was associated with a higher mortality rate in normotensive septic intensive care patients. Moreover, it was an independent predictor of ICU mortality.
Sepsis is a significant cause of mortality and morbidity and frequently associated with multiple organ failure. (1) Furthermore, it substantially consumes health care resources and expenditures. (16) To date, many parameters, including biochemical, (17) hematological, (18) demographic, (19) and imaging, (20) have been investigated to highlight the association between mortality and sepsis. Consistent with these studies, our study showed that older age and the proportions of hypertension and patients with IMV were significantly higher in non-survivors. However, our laboratory findings showed no significant difference, although some were associated with mortality in other reports. (17) Considering LV function, increasing evidence validates the correlation between myocardial dysfunction and high mortality rates in septic patients. (2) In a postmortem necropsy study on sepsis, fatal cardiovascular failure accounted for at least 35% of events, and myocardial injury was observed in more than half of the patients. (21) The most commonly used method to detect LV myocardial dysfunction is LVEF. (8) Nevertheless, its main limitation is the inability to detect subtle LV dysfunction, which is common in the early phase of sepsis. (8) Left ventricular global longitudinal strain measured by speckle tracking echocardiography permits a better estimate of LV systolic function, particularly subtle LV systolic dysfunction. (6) Numerous reports have evidenced the association between impaired LVGLS and mortality in patients with sepsis. (2,22) In our study, LVGLS was significantly worse in non-survivors than in survivors, while LVEF was similar between the two groups. Similar results were established by Chang et al. in septic shock patients. (8) Several pathophysiological processes in acute inflammatory states, including toxins, microvascular vasoconstriction, proinflammatory mediators, myocardial depressant factor, mitochondrial dysfunction, myocardial edema, inflammatory cell infiltration, and, consequently, myocardial injury, could lead to myocardial dysfunction. (21,23) Thus, impaired LVGLS in patients with sepsis may not be surprising.
Early detection of myocardial dysfunction and prediction of the prognosis in septic patients may be crucial for facilitating prioritized treatment and more aggressive therapeutic strategies. (7,20) Thus far, prognostic scoring systems such as GCS, (11) APACHE II, (13) and SOFA (12) have been defined to predict outcomes in critically ill patients. Similarly, all three risk scores were independent predictors of ICU mortality in our study.
As the most significant outcome of our work, we found that LVGLS was an independent predictor of ICU mortality. Several studies have investigated the predictive value of LVGLS in septic intensive care patients. Palmieri et al. considered the prognostic relevance of LVEF and LVGLS in sepsis, focusing on day-7 and day-28 followups. (24) Similar to our study, LVEF exhibited no prognostic relevance, whereas LVGLS was correlated with mortality.